Phase 1 JANX014 PSMA-directed CD3 T cell engager (tumor-activated, double-masked)

Janux Therapeutics’ first-in-human Phase 1, open-label, multicenter trial evaluates JANX014, a prostate-specific membrane antigen (PSMA)–directed CD3 T cell engager designed with “double-masking” so it is preferentially activated in the protease-rich tumor microenvironment, aiming to limit off-tumor T cell activation and cytokine release. The study uses a dose-escalation portion to define a tolerated dose (and characterize PK/PD), followed by dose expansion in metastatic castration-resistant prostate cancer (mCRPC), including patients who are later-line and progressing. The intervention is single-agent JANX014; mechanistically, it binds PSMA on tumor cells and CD3 on T cells to drive targeted T cell–mediated killing once unmasked in tumor tissue. The key angle is platform iteration: JANX014 extends Janux’s PSMA tumor-activated engager portfolio alongside its lead PSMA program (JANX007), testing whether enhanced safety margins and easier administration are achievable without losing anti-tumor activity. Today, mCRPC care typically sequences AR-pathway inhibitors, taxane chemotherapy, PARP inhibitors for HRR-altered disease, and PSMA radioligand therapy when eligible; this trial explores a novel immunotherapy option for patients after multiple prior lines.